This application is for a competitive renewal of the SRCS program of Dr. Pradeep K Dudeja. His program is focused on elucidating the mechanisms of regulation of electrolyte and fluid absorption in the human intestine in health and disease. His studies are aimed at understanding the pathophysiology of diarrheal diseases as it pertains to infectious diarrhea and inflammatory bowel diseases (IBD) associated diarrhea and to develop better therapeutic interventions. Diarrheal diseases are very common in our Veterans due to high incidence of IBD, infections and deployment related chronic illnesses and stress. Our program utilizes state-of-the-art approaches including human intestinal enteroids or mini guts and enteroid derived monolayers, organ-donor human intestine derived purified antipodal plasma membranes from various regions of the gut, in vitro molecular approaches and in vivo approaches utilizing knock out and transgenic mouse models to better understand the pathophysiology of diarrhea and to identify novel therapeutic targets. Our group has had a unique advantage of leading this field globally due to some of the pioneering techniques established by us using the organ donor human intestines. We have extensively published our work in over 220 original peer reviewed research articles in many prestigious journals in the field including Gastroenterology (impact factor 21) and J Clin Invest (12.3). We have also extensively defined the role of gut-microbe interactions in diarrheal diseases with respect to infectious diarrhea and the beneficial role of probiotics in these diseases. In addition, one of the key hallmarks of our program has been a multidisciplinary and collaborative nature of the research enterprise with a deep focus on mentoring new generation of VA and affiliated university investigators to enable them to establish their own independent research programs. We have been successful at both the fronts of making new discoveries in the field and mentoring new generation of young scientists and establishing a solid research environment at our local VA as well as at affiliated university. Our program has been continuously funded by multiple VA and NIH awards. This current application is intended to highlight the success of our program and requesting renewal of this SRCS program to continue the progress towards the new heights of success by nurturing and mentoring a new generation of investigators.